EP3094353B1 - Anticorps spécifique du rsv et parties fonctionnelles de ceux-ci - Google Patents

Anticorps spécifique du rsv et parties fonctionnelles de ceux-ci Download PDF

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EP3094353B1
EP3094353B1 EP15737068.5A EP15737068A EP3094353B1 EP 3094353 B1 EP3094353 B1 EP 3094353B1 EP 15737068 A EP15737068 A EP 15737068A EP 3094353 B1 EP3094353 B1 EP 3094353B1
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Prior art keywords
antibody
antigen
seq
chain variable
variable region
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EP3094353A4 (fr
EP3094353A2 (fr
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Nancy Ulbrandt
Nicole KALLEWAARD-LELAY
Andy Q. YUAN
Bettina Richter
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MedImmune LLC
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MedImmune LLC
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Priority to RS20200640A priority Critical patent/RS60387B1/sr
Application filed by MedImmune LLC filed Critical MedImmune LLC
Priority to EP20161884.0A priority patent/EP3741390A1/fr
Priority to EP23215838.6A priority patent/EP4353316A2/fr
Priority to SI201531183T priority patent/SI3094353T1/sl
Priority to PL15737068T priority patent/PL3094353T3/pl
Publication of EP3094353A2 publication Critical patent/EP3094353A2/fr
Publication of EP3094353A4 publication Critical patent/EP3094353A4/fr
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Priority to HRP20200607TT priority patent/HRP20200607T1/hr
Priority to HUS2300019C priority patent/HUS2300019I1/hu
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin

Definitions

  • This application relates to the field of biotechnology and medicine.
  • Respiratory Syncytial Virus is a common cold virus belonging to the family of paramyxovirus.
  • RSV is virulent, easily transmissible and the most common cause of lower respiratory tract disease in children of less than 2 years of age. Up to 98% of children attending day care will be infected in a single RSV season. Between 0.5% and 3.2% of children with RSV infection require hospitalization. Approximately 90,000 hospital admissions and 4,500 deaths per year were reported in United States. Major risk factors for hospitalization due to RSV are premature birth, chronic lung disease, congenital heart disease, compromised immunity, and age younger than 6 weeks in otherwise healthy children. There is a need for additional treatment for RSV positive bronchiolitis beside supportive care in the form of adequate nutrition and oxygen therapy.
  • Antiviral therapies such as Ribavirin have not been proven to be effective in RSV infection.
  • One monoclonal antibody, Palivizumab (also called Synagis®), is registered for prophylaxis against RSV infection.
  • Palivizumab is a genetically engineered (humanized) monoclonal antibody to the fusion protein of RSV. While Palivizumab has been a very effective prophylactic, alternative antibodies and therapies providing additional coverage against RSV would be advantageous.
  • US 2012/070446 discloses anti-RSV subtype A antibodies with an IC50 of 1.15 ng/ml.
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 28 L 30 E 31 D 37 V 61 G 81 M 82 E 84 S
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 19 K 23 K 28 T 29 F 30 S 37 V 45 L 81 M 82 E 84 S
  • the antibody or antigen-binding fragment thereof comprises the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 30 E 31 D 37 V 61 G 81 M 82 E 84 S 109 R
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 19 K 23 K 28 L 30 E 31 D 37 V 61 G 77 S 81 M 84 S 98 R
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 19 K 23 K 28 L 30 E 31 D 37 V 61 G 81 M 84 S
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 19 K 23 K 28 L 30 E 31 D 37 V 61 G 77 S 81 M 82 E 84 S
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Position relative to SEQ ID NO: 7 Amino Acid 19 K 23 K 28 L 30 E 31 D 37 V 61 G 77 S 81 M 84 S
  • the heavy chain variable region CDR1 sequence comprises DYIIN (SEQ ID NO: 9)
  • the heavy chain variable region CDR2 sequence comprises GIIPVLGTVHYGPKFQG (SEQ ID NO: 10)
  • the heavy chain variable region CDR3 sequence comprises ETALVVSTTYLPHYFDN (SEQ ID NO: 3) or ETALVVSTTYRPHYFDN (SEQ ID NO: 11).
  • the light chain variable region CDR1 sequence comprises QASQDIVNYLN (SEQ ID NO: 4)
  • the light chain variable region CDR2 sequence comprises VASNLET (SEQ ID NO: 5)
  • the light chain variable region CDR3 comprises QQYDNLP (SEQ ID NO: 6).
  • a synthetic, recombinant, or isolated antibody or antigen-binding fragment thereof capable of specifically binding to a RSV F antigen comprises
  • a synthetic, recombinant, or isolated antibody or a antigen-binding fragment thereof capable of specifically binding to a RSV F antigen comprises:
  • the antibody or antigen-binding fragment thereof has an Fc region having Y at position 252Y, T at position 254T, and E at position 256, wherein the numbering corresponds to the EU index in Kabat.
  • the antibody or antigen-binding fragment thereof is for use in a method of inhibiting RSV infection in a subject comprising administering the antibody or antigen-binding fragment thereof described herein to the subject.
  • Table 1 provides a listing of certain sequences referenced in present embodiments. Table 1 Description Sequence SEQ ID NO D25 HC CDR1 NYIIN 1 D25 HC CDR2 GIIPVLGTVHYAPKFQG 2 D25 HC CDR3 ETALVVSTTYLPHYFDN 3 D25 LC CDR1 QASQDIVNYLN 4 D25 LC CDR2 VASNLET 5 D25 LC CDR3 QQYDNLP 6 D25 heavy chain variable region 7 D25 light chain variable region 8 Alternative HC CDR1 DYIIN 9 Alternative HC CDR2 GIIPVLGTVHYGPKFQG 10 Alternative HC CDR3 ETALVVSTTYRPHYFDN 11 J variant heavy chain variable region 12 L variant heavy chain variable region 13 LA variant heavy chain variable region 14 1G7 heavy chain variable region 15 1F5 heavy chain variable region 16 2D10 heavy chain variable region 17 1G7-GLM heavy chain variable region 18 B12-1 heavy chain variable region 19 E3-5 heavy chain variable region 20 E9-2 heavy chain variable region
  • Antibodies or antigen-binding fragments thereof include, but are not limited to, polyclonal, monoclonal, human, humanized, or chimeric antibodies, single chain antibodies, epitope-binding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library.
  • Immunoglobulin or antibody molecules encompassed by this disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.
  • RSV-specific antibodies with improved properties over prior RSV-specific antibodies, including improved protection against RSV A subtypes and RSV B subtypes, improved neutralization, and lower IC50 values.
  • Such antibodies have a particular high or strong affinity for RSV and are therefore particularly suitable for counteracting and/or at least in part preventing an RSV infection and/or adverse effects of an RSV infection.
  • Antibodies and antigen-binding fragments thereof are synonymous with RSV-specific binding molecules and include any full length antibodies or antibody parts that are able to specifically bind RSV.
  • At least one nongermline residue of the heavy chain variable region of D25 (SEQ ID NO: 7) is changed to a germline residue.
  • at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 nongermline residues of the heavy chain variable region of D25 residues are switched back to a germline residue.
  • at least one nongermline residue may be changed to a germline residue and at least one CDR position may be modified relative to SEQ ID NO: 7.
  • the heavy chain variable region is at least 99% identical to SEQ ID NO: 15.
  • the antibody or antigen-binding fragment comprises a heavy chain variable region CDR3 sequence comprising a sequence which differs by one or two amino acids from ETALVVSTTYLPHYFDN (SEQ ID NO: 3) or ETALVVSTTYRPHYFDN (SEQ ID NO: 11).
  • the antibody or antigen-binding fragment thereof comprises all of the identical CDRs as SEQ ID NO: 8 (light chain).
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 sequence comprising DYIIN (SEQ ID NO: 9).
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR2 sequence comprising GIIPVLGTVHYGPKFQG (SEQ ID NO: 10).
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR3 sequence comprising ETALVVSTTYLPHYFDN (SEQ ID NO: 3) or ETALVVSTTYRPHYFDN (SEQ ID NO: 11).
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 sequence comprising DYIIN (SEQ ID NO: 9), a heavy chain variable region CDR2 sequence comprising GIIPVLGTVHYGPKFQG (SEQ ID NO: 10), and a heavy chain variable region CDR3 sequence comprising ETALVVSTTYLPHYFDN (SEQ ID NO: 3) or ETALVVSTTYRPHYFDN (SEQ ID NO: 11).
  • the antibody or antigen-binding fragment thereof comprises a light chain variable region CDR1 sequence comprises QASQDIVNYLN (SEQ ID NO: 4), a light chain variable region CDR2 sequence comprises VASNLET (SEQ ID NO: 5), and a light chain variable region CDR3 comprises QQYDNLP (SEQ ID NO: 6).
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region CDR1 sequence comprising DYIIN (SEQ ID NO: 9), a heavy chain variable region CDR2 sequence comprising GIIPVLGTVHYGPKFQG (SEQ ID NO: 10), a heavy chain variable region CDR3 sequence comprising ETALVVSTTYLPHYFDN (SEQ ID NO: 3) or ETALVVSTTYRPHYFDN (SEQ ID NO: 11), a light chain variable region CDR1 sequence comprising QASQDIVNYLN (SEQ ID NO: 4), a light chain variable region CDR2 sequence comprising VASNLET (SEQ ID NO: 5), and a light chain variable region CDR3 sequence comprising QQYDNLP (SEQ ID NO: 6).
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a sequence which is identical in the framework regions to SEQ ID NO: 15.
  • the antibody or antigen-binding fragment thereof comprises the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Table 2: J Variant Position relative to SEQ ID NO: 7 Amino Acid 37 V 81 M 82 E 84 S
  • the differences provided in Table 2 are not the only differences from SEQ ID NO: 7.
  • the light chain variable region comprises SEQ ID NO: 8.
  • the antibody or antigen-binding fragment thereof comprises the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Table 3: L Variant Position relative to SEQ ID NO: 7 Amino Acid 37 V 45 L 81 M 82 E 84 S
  • the differences provided in Table 3 are not the only differences from SEQ ID NO: 7.
  • the light chain variable region comprises SEQ ID NO: 8.
  • the antibody or antigen-binding fragment thereof comprises at least the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Table 4: 1G7 Position relative to SEQ ID NO: 7 Amino Acid 28 L 30 E 31 D 37 V 61 G 81 M 82 E 84 S
  • the differences provided in Table 4 are not the only differences from SEQ ID NO: 7.
  • the light chain variable region comprises SEQ ID NO: 8.
  • the antibody or antigen-binding fragment comprises the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Table 5: 1F5 Position relative to SEQ ID NO: 7 Amino Acid 30 E 31 D 37 V 61 G 81 M 82 E 84 S
  • the differences provided in Table 5 are not the only differences from SEQ ID NO: 7.
  • the light chain variable region comprises SEQ ID NO: 8.
  • the antibody or antigen-binding fragment thereof comprises the following amino acids in the heavy chain variable region that differ from SEQ ID NO: 7: Table 6: 2D10 Position relative to SEQ ID NO: 7 Amino Acid 30 E 31 D 37 V 61 G 81 M 82 E 84 S 109 R 7.
  • the differences provided in Table 6 are not the only differences from SEQ ID NO: 7.
  • the light chain variable region comprises SEQ ID NO: 8.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence comprising a sequence which is at least 98%, 99%, or 100% identical to the sequence of SEQ ID NO: 15.
  • the antibody or antigen-binding fragment thereof comprises a heavy chain sequence variable region comprising a sequence which is at least 99%, or 100% identical to the framework (i.e., non CDR) sequence of SEQ ID NO: 15.
  • the antibody or antigen-binding fragment thereof comprises a light chain variable region sequence comprising a sequence which is identical to the sequence DIQMTQSPSSLSAAVGDRVTIT
  • a conservative amino acid substitution is applied.
  • Conservative amino acid substitution involves substitution of one amino acid with another with generally similar properties (size, hydrophobicity, etc.) such that the overall functioning is likely not to be seriously affected.
  • the antibody or antigen-binding fragment thereof comprises the first two, or all three of the changes in Table 7.
  • Table 7 Position relative to SEQ ID NO: 7 Type of Change Amino Acid 31 CDR modification D 61 CDR modification G 109 CDR modification R
  • additional modifications may be made to antibodies or antigen-binding fragment thereof described herein to improve their half-life.
  • mutations such as deletion, addition, or substitution mutations may be made to the antibodies or antigen-binding fragment thereof to improve their half-life.
  • the Fc region may be mutated to include one, two, or all three of the following substitutions M252Y, S254T, and T256E, wherein the numbering corresponds to the EU index in Kabat.
  • the Fc region may be mutated to include all of the following substitutions M252Y, S254T, and T256E, wherein the numbering corresponds to the EU index in Kabat.
  • the antibody or antigen-binding fragment thereof has an Fc region having Y at position 252Y, T at position 254T, and E at position 256, wherein the numbering corresponds to the EU index in Kabat.
  • the antibody or antigen-binding fragment thereof has an IC50 value of less than 10 ng/ml in an in vitro neutralization assay wherein HEp-2 cells are infected with RSV.
  • the IC50 is 9 ng/ml, 8 ng/ml, 7 ng/ml, 6 ng/ml, 5 ng/ml, 4 ng/ml, 3 ng/ml, or 2 ng/ml or less for RSV subtype A and/or RSV subtype B.
  • the IC50 is measured in the in vitro neutralization assay described in the examples, optionally for RSV A2 and/or RSV B9320.
  • the antibodies and antigen-binding fragments thereof are effective at neutralizing both RSV subtype A and B strains.
  • the term antibody or antigen-binding fragment thereof is used in the broadest sense. It may be man-made such as monoclonal antibodies (mAbs) produced by conventional hybridoma technology, recombinant technology and/or an antigen-binding fragment thereof. It may include both intact immunoglobulin molecules for example a polyclonal antibody, a monoclonal antibody (mAb), a monospecific antibody, a bispecific antibody, a polyspecific antibody, a human antibody, a humanized antibody, an animal antibody (e.g.
  • the antigen-binding fragment thereof is a single chain antibody, a single chain variable fragment (scFv), a Fab fragment, or a F(ab') 2 fragment.
  • an antibody or antigen-binding fragment thereof is said to be "capable of binding" a molecule if it is capable of specifically reacting with the molecule to thereby bind the molecule to the antibody.
  • Antibody fragments or portions may lack the Fc fragment of intact antibody, clear more rapidly from the circulation, and may have less non-specific tissue binding than an intact antibody.
  • Examples of antibody may be produced from intact antibodies using methods well known in the art, for example by proteolytic cleavage with enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab') 2 fragments).
  • Portions of antibodies may be made by any of the above methods, or may be made by expressing a portion of the recombinant molecule.
  • the CDR region(s) of a recombinant antibody may be isolated and subcloned into an appropriate expression vector.
  • an antibody or antigen-binding fragment thereof is a human antibody or antibody fragment.
  • the use of human antibodies for human therapy may diminish the chance of side effects due to an immunological reaction in a human individual against nonhuman sequences.
  • the antibody or antigen-binding fragment thereof is humanized.
  • an antibody or antigen-binding fragment thereof is a chimeric antibody. This way, sequences of interest, such as for instance a binding site of interest, can be included into an antibody or antigen-binding fragment thereof.
  • the antibody may have an IgG, IgA, IgM, or IgE isotype. In one embodiment, the antibody is an IgG.
  • the present teaching further discloses an isolated, synthetic, or recombinant nucleic acid sequence encoding any of the antibodies or antigen-binding fragments thereof described in section I.A or I.B above.
  • nucleic acid is for instance isolated from a B-cell which is capable of producing an antibody or functional part.
  • nucleic acids encode the heavy and light chain sequences set forth herein.
  • nucleic acids encode heavy and light chain sequences comprising the heavy and light chain CDRs, respectively, set forth herein.
  • the nucleic acids will encode antigen-binding fragments of the antibodies described herein. Due to the degeneracy of the nucleic acid code, multiple nucleic acids will encode the same amino acid and all are encompassed herein.
  • an antibody or an antigen-binding fragment thereof may be used in a method of treatment or as a medicine.
  • the method may be used for counteracting or at least in part preventing an RSV infection or for counteracting or at least in part preventing adverse effects of an RSV infection.
  • the method also comprises administering to an individual in need thereof a therapeutically effective amount of an antibody or antigen-binding fragment thereof as described herein.
  • the individual in need thereof is a human patient.
  • an antibody or antigen-binding fragment thereof in order to counteract RSV, may be administered to an individual before an RSV infection has taken place, in other words as a prophylactic agent.
  • an antibody or antigen-binding fragment thereof may be administered when an individual is already infected by RSV.
  • Said antibody or antigen-binding fragment thereof may be administered to individuals with an increased risk of RSV infection, such as for instance children with premature birth, individuals with chronic lung disease, congenital heart disease and/or compromised immunity, children with an age younger than 6 weeks.
  • Children with premature birth include both infants in their first year of life, as well as children in their second year of life and older children who remain at risk of RSV infection.
  • elderly people have an increased risk of RSV infection and thus may be targeted for administration based on risk.
  • the antibodies or antigen-binding fragment thereof may also be administered to individuals who have had a prior RSV infection.
  • antibodies or antigen-binding fragment thereof are typically combined with a pharmaceutically acceptable carrier, adjuvant, diluent and/or excipient.
  • the antibodies or antigen-binding fragment thereof are combined with water for injection, In another embodiment, they are prepared in a sterile, preservative-free liquid solution with histidine, glycine, and chloride.
  • suitable carriers for instance comprise keyhole limpet haemocyanin (KLH), serum albumin (e.g. BSA or RSA) and ovalbumin.
  • KLH keyhole limpet haemocyanin
  • serum albumin e.g. BSA or RSA
  • ovalbumin e.g. BSA or RSA
  • said suitable carrier comprises a solution like for example saline.
  • the antibodies or antigen-binding fragment thereof are provided in a lyophilized form and mixed with water for injection prior to administration.
  • nucleic acid encoding an antibody or antigen-binding fragment thereof may be administered. Upon administration of such nucleic acid, antibodies or antigen-binding fragment thereof are produced by the host's machinery. Produced antibodies or antigen-binding fragment thereof are capable of preventing and/or counteracting RSV infection and/or the adverse effects of an RSV infection.
  • the antibodies or antigen-binding fragment thereof described herein may be manufactured from a hybridoma that secretes the antibody or from a recombinantly produced cell that has been transformed or transfected with a gene or genes encoding the antibody or antigen-binding fragment thereof.
  • One teaching includes a method of producing the antibody or antigen-binding fragment thereof by culturing host cells under conditions wherein a nucleic acid is expressed to produce the antibody, followed by recovering the antibody.
  • a variety of cell lines may be used for expressing the antibody or antigen-binding fragment thereof, including, but not limited to, mammalian cell lines.
  • the cell lines may be human.
  • bacterial or insect cell lines may be used.
  • the cell lines include Chinese hamster ovary (CHO) cells, variants of CHO cells (for example DG44), 293 cells and NSO cells.
  • cell lines include VERY, BHK, Hela, COS, MDCK, 293F, 293T, 3T3, W138, BT483, Hs578T, HTB2, BT2O and T47D, CRL7O3O and HsS78Bst cells.
  • Recombinant expression utilizes construction of an expression vector containing a polynucleotide that encodes the antibody or antigen-binding fragment thereof.
  • a vector for the production of the antibody may be produced by recombinant DNA technology well known in the art.
  • Expression vectors may include appropriate transcriptional and translational control signals. This may be accomplished using in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination.
  • a replicable vector comprises a nucleic acid sequence encoding an antibody or antigen-binding fragment thereof operably linked to a heterologous promoter.
  • a variety of host-expression vector systems may be utilized to express antibodies or antigen-binding fragment thereof as described in U.S. Pat. No. 5,807,715 .
  • mammalian cells such as Chinese hamster ovary cells (CHO), in conjunction with a vector such as the major intermediate early gene promoter element from human cytomegalovirus, are an effective expression system for antibodies ( Foecking et al., Gene, 45:101 (1986 ); and Cockett et al., Bio/Technology, 8:2 (1990 )).
  • a host cell strain may be chosen which modulates the expression of inserted sequences, or modifies and processes the gene product in the specific fashion desired.
  • Such modifications e.g., glycosylation
  • processing e.g., cleavage
  • protein products may be important for the function of the protein.
  • Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the protein of the invention.
  • eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used.
  • a number of expression vectors may be selected depending upon the use intended for the antibody or antigen-binding fragment thereof being expressed. For example, when a large quantity of such an antibody or antigen-binding fragment thereof is to be produced, for the generation of pharmaceutical compositions comprising an antibody or antigen-binding fragment thereof, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable.
  • vectors include, but are not limited to, the E.
  • coli expression vector pUR278 ( Ruther et al., EMBO, 12:1791 (1983 )), in which the coding sequence may be ligated individually into the vector in frame with the lac Z coding region so that a fusion protein is produced; pIN vectors ( Inouye & Inouye, 1985, Nucleic Acids Res. 13:3101-3109 (1985 ); Van Heeke & Schuster, 1989, J. Biol. Chem., 24:5503-5509 (1989 )); and the like.
  • pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione-S-transferase (GST).
  • fusion proteins are soluble and can easily be purified from lysed cells by adsorption and binding to glutathione-agarose affinity matrix followed by elution in the presence of free glutathione.
  • the pGEX vectors are designed to introduce a thrombin and/or factor Xa protease cleavage sites into the expressed polypeptide so that the cloned target gene product can be released from the GST moiety.
  • Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes.
  • the virus grows in Spodoptera frugiperda cells.
  • the protein coding sequence may be cloned individually into non-essential regions (for example, the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example, the polyhedrin promoter).
  • a number of virus based expression systems may be utilized.
  • the coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence.
  • This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion into a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody or antigen-binding fragment thereof in infected hosts (e.g., see, Logan & Shenk, Proc.
  • Specific initiation signals may also be required for efficient translation of inserted antibody or antigen-binding fragment thereof coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon should generally be in frame with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bittner et al., Methods in Enzymol., 153:51-544(1987 )).
  • Stable expression can be used for long-term, high-yield production of recombinant proteins.
  • cell lines which stably express the protein molecule may be generated.
  • Host cells can be transformed with an appropriately engineered vector comprising expression control elements (e.g., promoter, enhancer, transcription terminators, polyadenylation sites, etc.), and a selectable marker gene.
  • expression control elements e.g., promoter, enhancer, transcription terminators, polyadenylation sites, etc.
  • cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media.
  • the selectable marker in the recombinant plasmid confers resistance to the selection and allows cells that stably integrated the plasmid into their chromosomes to grow and form foci which in turn can be cloned and expanded into cell lines.
  • Plasmids that encode an antibody or antigen-binding fragment thereof can be used to introduce the gene/cDNA into any cell line suitable for production
  • a number of selection systems may be used, including, but not limited to, the herpes simplex virus thymidine kinase ( Wigler et al., Cell, 11:223 (1977 )), hypoxanthineguanine phosphoribosyltransferase ( Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA, 48:202 (1992 )), and adenine phosphoribosyltransferase ( Lowy et al., Cell, 22:8-17 (1980 )) genes can be employed in tk-, hgprt- or aprT-cells, respectively.
  • antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate ( Wigler et al., Natl. Acad. Sci. USA, 77:357 (1980 ); O'Hare et al., Proc. Natl. Acad. Sci. USA, 78:1527 (1981 )); gpt, which confers resistance to mycophenolic acid ( Mulligan & Berg, Proc. Natl. Acad. Sci. USA, 78:2072 (1981 )); neo, which confers resistance to the aminoglycoside G-418 ( Wu and Wu, Biotherapy 3:87-95 (1991 ); Tolstoshev, Ann. Rev.
  • an antibody or antigen-binding fragment thereof may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigens Protein A or Protein G, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • chromatography e.g., ion exchange, affinity, particularly by affinity for the specific antigens Protein A or Protein G, and sizing column chromatography
  • centrifugation e.g., centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • the proteins of the present invention or antigen-binding fragments thereof may be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.
  • RSV-specific antibody producing cells are generated which are stable for at least six months.
  • an RSV-specific antibody producing cell is stable for at least nine weeks, at least three months, or at least six months.
  • alternative methods of making antibodies and antigen-binding fragment thereof are well known in the art and described in at least US Pat. No. 8,562,996 .
  • VL immunoglobulin variable light chain
  • VH variable heavy chain
  • human IgGlexpression vector containing the kappa light constant region and the CH1-hinge-CH2-CH3 IgG1 heavy constant region.
  • human embryonic kidney 293-F cells were transiently transfected with the 1G7-containing vector using 293FectinTM reagent (Invitrogen, Carlsbad, CA). Cells were grown at 37°C, 120 rpm with 5% CO 2 and 80% humidity. The culture media was fed on the second day by adding equal volume media and harvested 10 days post transfection.
  • the supernatant was sterile filtered to remove cells and debris.
  • the IgG was purified using protein A column (Hi-trap protein A column, Sigma) and eluted protein was dialyzed against PBS overnight at 4°C. The IgG concentration was determined by protein quantitation in NanoDrop (Thermo Scientific).
  • Microneutralization assays were performed as follows: Briefly, 2-fold serial dilutions of MAb were introduced into 384-well microtiter plates in HEp-2 cell culture medium at a volume of 15 ⁇ L/well. Subsequently, 15 ⁇ L of either RSV A2 or RSV B 9320 virus diluted into HEp-2 cell culture medium to concentration ranging from 80 to 150 pfu/well and was added to each well including control wells containing HEp-2 cell culture medium alone, and plates were incubated for 1.5 hours at 37°C with 5% CO2. HEp-2 cells were added at 2.5 x 10 5 cells/mL in 30 ⁇ L to each well and the plates were incubated at 37°C with 5% CO2. After 3 days for RSV A2 or 4 days for RSV B9320, medium was removed and 30 ⁇ L of ice cold 80% acetone/20% PBS was added to fix the cells.
  • Viral replication was measured by enzyme-linked immunosorbent assay (ELISA) using a horseradish peroxidase conjugated anti-RSV F MAb targeting the C site of RSV F (1331H) ( Beeler and van Wyke Coelingh, J Virol. 63(7):2941-2950 (1989 ). 1331H MAb was diluted 1:6,000 in PBS and 30 ⁇ l was added to each well. Following two hours of incubation at 37°C, the plates were washed three times with PBS-T. TMB peroxidase 30 ⁇ L was added to each well and the plates were incubated at room temperature in the dark for 15 minutes. The reaction was stopped by the addition of 15 ⁇ L of 2N H2SO4 to each well.
  • ELISA enzyme-linked immunosorbent assay
  • Substrate turnover was measured by monitoring absorbance at 450 nm using a microplate reader.
  • IC50 values were calculated using a non-linear fit algorithm in Graphpad Prism using the log (inhibitor) vs. response with variable slope curve fit and represent the concentration of MAb required for a 50% reduction in absorbance measured at 450 nm.
  • Results are provided in Figure 4 , which shows that 1G7, 1F5, 2D10, and D25 each inhibited RSV A2 and RSV B9320 replication in the microneutralization. 1G7 was the most effective, followed by 1F5, 2D10, and then D25.
  • Animals were dosed with 0.1 ml of antibody by intramuscular injection at the various dosage levels indicated in the figure. Twenty-four hours later, animals were anesthetized using an isoflourane chamber and infected by intranasal instillation of 1 ⁇ 10 6 pfu/animal of RSV strain A2. Four days later, animals were sacrificed by carbon dioxide asphyxiation; their lungs were surgically removed, bisected and frozen in liquid nitrogen or processed immediately. Blood samples were obtained by cardiac puncture at the time of sacrifice.
  • RSV viral titer in cotton rat lung homogenates were determined for each dose group.
  • harvested lungs were individually homogenized in 10 parts (weight/volume) Hanks Balanced Salt Solution plus sucrose phosphate using a Fast Prep 24 tissue homogenizer for 20 seconds with TeenALysing Matrix tubes at room temperature.
  • the resulting suspensions were centrifuged at 930 ⁇ g for 10 min at 4°C, and the supernatants were collected and stored at - 80°C until analysis.
  • Lung homogenate samples were diluted 1:10 and 1:100 in culture medium, and 50 ⁇ L of either undiluted lung homogenate or diluted lung homogenate samples were added to duplicate wells of HEp-2 cells that had been seeded at a cell density of 2.5 ⁇ 10 5 cells/well in 24-well plates, 24 hours prior to inoculation. After 1 hour incubation at 37°C with 5% CO 2 , the inoculum was replaced with culture medium containing 0.8% methylcellulose and the cells were incubated at 37°C with 5% CO 2 . Five days later the overlay was removed, and the cells were fixed and immuno-stained with an goat anti-RSV polyclonal antibody followed by a secondary anti-goat HRP antibody.
  • Plaques were visualized by reaction with AEC reagent. Plaques were quantified under a microscope using a 10 ⁇ objective. The limit of detection for this assay is 200 pfu/g of tissue. Samples with a viral titer below the limit of detection ( ⁇ 200 pfu/g) were designated at 100 pfu/g (one-half of the lower limit of detection) for purposes of the statistical analysis. Results are provided in Figure 5 , demonstrating that the J, L, and LA variants are all more effective than D25 in protecting against RSV A challenge, but that the L and LA variants were less effective in protecting against RSV B subtypes (with L performing better against one B strain than another). Based on this data, J was chosen as the starting point for further optimization.
  • the concentrations of human IgG in cotton rat serum samples on the day of lung harvest were determined using an ELISA method.
  • the human antibodies were captured by a goat anti-human antibody bound to microtiter plates.
  • the goat anti-human IgG (H + L) antibody (0.5 ⁇ g/mL in 1 ⁇ PBS) was coated onto Nunc Maxisorp 384 well microtiter plates overnight at 4°C in a 30 ⁇ L volume. Plates were washed then blocked with 60 ⁇ L of a solution of PBS + 3% heat inactivated goat serum for 1 hour at room temperature.
  • the blocking buffer was removed and samples were applied as follows: A two-fold serial dilution of the standard human antibody diluted in assay buffer was used for the standard curve with a concentration range of 500 ng/ml to 0.488 ng/ml. Standard curves were fitted using a 4 parameter curve fit.
  • Results are provided in Figure 8 , showing that the variants described herein have lower IC50s than D25 in neutralizing both RSV A2 and RSV B9320. This also demonstrates that there was no loss of activity against the A2 or B9320 virus with increased activity seen with E9-2 and B12-1 and only a nominal loss of activity against the B9320 virus with 1G7 GLM and E3-5.
  • RSV A and RSV B virus mutants were isolated by passage three times in the presence of 250 ng/ml of 1G7-YTE.
  • 1G7-YTE is the 1G7 antibody with the YTE mutation described above in section I.C above.
  • the sequence of the RSV F protein was determined. Mutations correspond to regions that were previously defined in the co-crystal structure of RSV F with the parental D25 antibody. All resistant mutants contained changes in the region of RSV F protein in the F1 region between amino acids 200-213. Secondary mutations at position 294 were not shown to enhance resistance and were no more resistant than those with a single mutation in the region 200-213. Secondary mutations in the F2 region of the N208S mutation background resulted in enhanced resistance. Results are provided in Figure 9 .
  • a neutralization assay was performed by pre-incubation of the expanded clinical isolate viruses with a dilution series of the antibodies prior to infection of HEp2 cells. Infection of cells was measured as a function of F protein expression on the surface of the cells. IC50 values were calculated by non-linear fitting of neutralization curves. Viral replication was measured as in Example 2 (In Vitro Microneutralization Assay).
  • Results are provided in Figure 10 .
  • the IC50 for 1G7 and 1F5 are both lower than D25 for neutralizing either A isolates or B isolates of RSV in HEp2 cells.

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Claims (5)

  1. Anticorps ou fragment de liaison à l'antigène de celui-ci, l'anticorps ou le fragment de liaison à l'antigène de celui-ci se fixant spécifiquement au Virus Respiratoire Syncytial (RSV) et étant efficace pour la neutralisation des souches A ainsi que B de sous-type du RSV, et comprenant :
    une région variable de chaîne lourde qui possède au moins 98% d'identité avec SEQ ID n° 15 et une région variable de chaîne légère qui est identique à SEQ ID n° 8,
    où la séquence de région variable de chaîne lourde CDR1 comprend DYIIN (SEQ ID n° 9), la séquence de région variable de chaîne lourde CDR2 comprend GIIPVLGTVHYGPKFQG (SEQ ID n° 10), et la séquence de région variable de chaîne lourde CDR3 comprend une séquence qui est identique à, ou diffère au niveau d'un ou deux acides aminés par rapport à, ETALVVSTTYLPHYFDN (SEQ ID n° 3) ou ETALVVSTTYRPHYFDN (SEQ ID n° 11), et
    où la région variable de chaîne lourde comprend en outre les acides aminés suivants, qui diffèrent de SEQ ID n° 7 : Position par rapport à SEQ ID n° 7 Acide Aminé 30 E 31 D 37 V 61 G 81 M 82 E 84 S
  2. Anticorps ou fragment de liaison à l'antigène selon la revendication 1, comprenant une région variable de chaîne lourde qui possède au moins 99% d'identité avec SEQ ID n° 15.
  3. Anticorps ou fragment de liaison à l'antigène selon la revendication 1, l'anticorps ou le fragment de liaison à l'antigène de celui-ci comprenant un isotype de l'IgG1 humaine et comprenant une région Fc comprenant Y au niveau de la position 252, T au niveau de la position 254, et E au niveau de la position 256, où la numérotation correspond à l'indice EU dans Kabat.
  4. Fragment de liaison à l'antigène selon la revendication 1, le fragment de liaison à l'antigène étant un anticorps à chaîne unique, un fragment variable à chaîne unique (scFv), un fragment Fab, ou un fragment F(ab')2.
  5. Anticorps ou fragment de liaison à l'antigène de celui-ci selon l'une quelconque des revendications précédentes, pour une utilisation dans une méthode destinée à prévenir ou traiter une infection par le RSV.
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